This Mentored Research Scientist Development Award describes a research and training program that will prepare the applicant, Elizabeth Lippard, PhD, to transition to an independent investigator with a research program focused on biomarkers (clinical, behavioral, and neural) in bipolar disorder and interactions between acute alcohol intoxication and altered brain development. Essential to successfully improving clinical prognosis in bipolar disorder are research results that enable better prediction, diagnosis, and treatment based on the individual. The applicant?s proposal addresses the need for scientists working to understand mechanisms that contribute to individual differences in disease course. The applicant will investigate biomarkers predictive of risk for alcohol use problems in people with bipolar disorder. We hypothesize that developmental abnormalities in bipolar disorder that disrupt ventral prefrontal network function, and that likely underlie the development of the illness, also increase the risk for alcohol use/disorders by altering sensitivity to alcohol. A comprehensive research and training plan has been created with mentors, Stephen Strakowski, MD, Kim Fromme, PhD, and Cameron Craddock, PhD, at the University of Texas at Austin, to test this hypothesis. Primary training objectives are to: 1) obtain clinical training in the diagnosis and clinical assessment of bipolar disorder and alcohol use disorders; 2) extend the applicant?s methodological repertoire to include advanced functional magnetic resonance imaging (fMRI); and 3) train in placebo-controlled alcohol administration methods. These objectives are a natural extension of the applicant?s background employing structural neuroimaging and behavioral testing in bipolar disorder to investigate neuroanatomical and behavioral predictors of mood- and alcohol-related problems and her preclinical work on alcohol self-administration in rodent models. Research aims are to (Aim 1) identify individual differences in the experience of stimulating, sedating, and anxiolytic effects of alcohol and (Aim 2) assess alcohol-induced changes in neural responses to emotional stimuli in bipolar and healthy young adults. In the proposed research, 60 young adults (50% with bipolar disorder, 50% female) will be clinically phenotyped and complete structural MRI scans. Then, following standard beverage administration procedures, participants will complete measures of subjective response to alcohol and fMRI scans while under the influence of alcohol or a placebo (within-person, counter-balanced). We predict individuals with bipolar disorder will report lower subjective response to alcohol, compared with healthy participants, with lower response associated with altered function in ventral prefrontal networks. Relationships with alcohol use patterns will be investigated. This K01 award is critical to pursue the advanced training to test our hypothesis and for the applicant to transition to an independent investigator with a research program utilizing advanced fMRI approaches in the fields of bipolar disorder and alcohol use/disorders. Findings will inform new, specific targets for early detection of risk and prevention.